Chronic conditions, late mortality, and health status after childhood AML: a Childhood Cancer Survivor Study report.

Five-year survival following childhood acute myeloid leukemia (AML) has increased following improvements in treatment and supportive care. Long-term health outcomes are unknown. To address this, cumulative incidence of late mortality and grades 3 to 5 chronic health condition (CHC) were estimated among 5-year AML survivors diagnosed between 1970 and 1999. Survivors were compared by treatment group (hematopoietic cell transplantation [HCT], chemotherapy with cranial radiation [chemo + CRT], chemotherapy only [chemo-only]), and diagnosis decade. Self-reported health status was compared across treatments, diagnosis decade, and with siblings. Among 856 survivors (median diagnosis age, 7.1 years; median age at last follow-up, 29.4 years), 20-year late mortality cumulative incidence was highest after HCT (13.9%; 95% confidence interval [CI], 10.0%-17.8%; chemo + CRT, 7.6%; 95% CI, 2.2%-13.1%; chemo-only, 5.1%; 95% CI, 2.8%-7.4%). Cumulative incidence of mortality for HCT survivors diagnosed in the 1990s (8.5%; 95% CI, 4.1%-12.8%) was lower vs those diagnosed in the 1970s (38.9%; 95% CI, 16.4%-61.4%). Most survivors did not experience any grade 3 to 5 CHC after 20 years (HCT, 45.8%; chemo + CRT, 23.7%; chemo-only, 27.0%). Furthermore, a temporal reduction in CHC cumulative incidence was seen after HCT (1970s, 76.1%; 1990s, 38.3%; P = .02), mirroring reduced use of total body irradiation. Self-reported health status was good to excellent for 88.2% of survivors; however, this was lower than that for siblings (94.8%; P < .0001). Although HCT is associated with greater long-term morbidity and mortality than chemotherapy-based treatment, gaps have narrowed, and all treatment groups report favorable health status.

Factors influencing risk-based care of the childhood cancer survivor in the 21st century.

The population of adult survivors of childhood cancer continues to grow as survival rates improve. Although it is well established that these survivors experience various complications and comorbidities related to their malignancy and treatment, this risk is modified by many factors that are not directly linked to their cancer history. Research evaluating the influence of patient-specific demographic and genetic factors, premorbid and comorbid conditions, health behaviors, and aging has identified additional risk factors that influence cancer treatment-related toxicity and possible targets for intervention in this population. Furthermore, although current long-term follow-up guidelines comprehensively address specific therapy-related risks and provide screening recommendations, the risk profile of the population continues to evolve with ongoing modification of treatment strategies and the emergence of novel therapeutics. To address the multifactorial modifiers of cancer treatment-related health risk and evolving treatment approaches, a patient-centered and risk-adapted approach to care that often requires a multidisciplinary team approach, including medical and behavioral providers, is necessary for this population. CA Cancer J Clin 2018;68:133-152. © 2018 American Cancer Society.

The burden of cardiovascular disease and risk for subsequent major adverse cardiovascular events in survivors of childhood cancer: a prospective, longitudinal analysis from the St Jude Lifetime Cohort Study.

BACKGROUND: The effect of the increasing lifetime burden of non-major cardiovascular conditions on risk for a subsequent major adverse cardiovascular event among survivors of childhood cancer has not been assessed. We aimed to characterise the prevalence of major adverse cardiovascular events and their association with the cumulative burden of non-major adverse cardiovascular events in childhood cancer survivors. METHODS: This is a longitudinal cohort study with participant data obtained from an ongoing cohort study at St Jude Children's Research Hospital: the St Jude Lifetime Cohort Study (SJLIFE). Prospective clinical follow-up was of 5-year survivors of childhood cancer who were diagnosed when aged younger than 25 years from 1962 to 2012. Age-frequency, sex-frequency, and race-frequency matched community-control participants completed a similar one-time clinical assessment. 22 cardiovascular events were graded using a St Jude Children's Research Hospital-modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Cumulative incidence and burden of the primary outcome of major adverse cardiovascular events (cardiomyopathy, myocardial infarction, stroke, and other cardiovascular-related mortality) were estimated. Rate ratios (RR) of the association of major adverse cardiovascular events with 22 non-major adverse cardiovascular events were estimated using multivariable piecewise-exponential regression adjusting for attained age, age at diagnosis, sex, race and ethnicity, treatment era, diagnosis of diabetes, and exposure to cardiotoxic cancer therapies. The St Jude Lifetime Cohort study is registered with ClinicalTrials.gov, NCT00760656, and is ongoing. FINDINGS: 9602 5-year survivors of childhood cancer, and 737 community controls were included in the longitudinal follow-up (from Sept 13, 2007, to Dec 17, 2021). The median follow-up was 20·3 years (IQR 12·0-31·4) from the date of primary cancer diagnosis (4311 [44.9%] were females). By the age of 50 years (analysis stopped at age 50 years due to the low number of participants older than that age), the cumulative incidence of major adverse cardiovascular events among survivors was 17·7% (95% CI 15·9-19·5) compared with 0·9% (0·0-2·1) in the community controls. The cumulative burden of major adverse cardiovascular events in survivors was 0·26 (95% CI 0·23-0·29) events per survivor compared with 0·009 (0·000-0·021) events per community control participant. Increasing cumulative burden of grade 1-4 non-major adverse cardiovascular events was associated with an increased future risk of major adverse cardiovascular events (one condition: RR 4·3, 95% CI 3·1-6·0; p<0·0001; two conditions: 6·6, 4·6-9·5; p<0·0001; and three conditions: 7·7, 5·1-11·4; p<0·0001). Increased risk for major adverse cardiovascular events was observed with specific subclinical conditions (eg, grade 1 arrhythmias [RR 1·5, 95% CI 1·2-2·0; p=0·0017]), grade 2 left ventricular systolic dysfunction (2·2, 1·6-3·1; p<0·0001), grade 2 valvular disorders (2·2, 1·2-4·0; p=0·013), but not grade 1 hypercholesterolaemia, grade 1-2 hypertriglyceridaemia, or grade 1-2 vascular stenosis. INTERPRETATION: Among an ageing cohort of survivors of childhood cancer, the accumulation of non-major adverse cardiovascular events, including subclinical conditions, increased the risk of major adverse cardiovascular events and should be the focus of interventions for early detection and prevention of major adverse cardiovascular events. FUNDING: The US National Cancer Institute and the American Lebanese Syrian Associated Charities.

Sugar and sugar-sweetened beverages in relation to premature aging in adult survivors of childhood cancer.

BACKGROUND: Premature aging is a significant concern in adult survivors of childhood cancer as they develop aging-related conditions at a younger age than their peers with no history of childhood cancer. Although modifiable lifestyle factors, such as diet, are postulated to affect aging process, supporting evidence is sparse. METHODS: We examined if the consumption of sugar and sugar-sweetened beverages was related to premature aging in 3322 adult survivors of childhood cancer in the St. Jude Lifetime Cohort. Premature aging was assessed using the Deficit Accumulation Index (DAI) that was a ratio of the number of age-related chronic health conditions each survivor had out of 44 conditions total. Multinomial logistic regressions adjusting for confounders were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: There were 46% of childhood cancer survivors consumed SSBs once or more times per day. High intake of sugar, especially sugars added to foods during preparation or processing, and habitual consumption of sugar-sweetened beverage were associated with an increased risk of premature aging. DISCUSSION: Our findings support a need to include strategies to reduce sugar and sugar-sweetened beverages consumption in lifestyle interventions to promote healthy aging in adult survivors of childhood cancer.

Quantitative computed tomography analysis of body composition changes in paediatric patients with acute lymphoblastic leukaemia.

Children with acute lymphoblastic leukaemia (ALL) are at risk for obesity and cardiometabolic diseases. To gain insight into body composition changes among children with ALL, we assessed quantitative computed tomography (QCT) data for specific body compartments (subcutaneous adipose tissue [SAT], visceral adipose tissue [VAT], total adipose tissue [TAT], lean tissue [LT], LT/TAT and VAT/SAT at lumbar vertebrae L1 and L2) at diagnosis and at off-therapy for 189 children with ALL and evaluated associations between body mass index (BMI) Z-score and clinical characteristics. BMI Z-score correlated positively with SAT, VAT and TAT and negatively with LT/TAT and VAT/SAT. At off-therapy, BMI Z-score, SAT, VAT and TAT values were higher than at diagnosis, but LT, LT/TAT and VAT/SAT were lower. Patients aged ≥10 years at diagnosis had higher SAT, VAT and TAT and lower LT and LT/TAT than patients aged 2.0-9.9 years. Female patients had lower LT and LT/TAT than male patients. Black patients had less VAT than White patients. QCT analysis showed increases in adipose tissue and decreases in LT during ALL therapy when BMI Z-scores increased. Early dietary and physical therapy interventions should be considered, particularly for patients at risk for obesity.

Specific causes of excess late mortality and association with modifiable risk factors among survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort.

BACKGROUND: 5-year survival after childhood cancer does not fully describe life-years lost due to childhood cancer because there are a large number of deaths occurring beyond 5-years (late mortality) related to cancer and cancer treatment. Specific causes of health-related (non-recurrence, non-external) late mortality and risk reduction through modifiable lifestyle and cardiovascular risk factors are not well described. Through using a well-characterised cohort of 5-year survivors of the most common childhood cancers, we evaluated specific health-related causes of late mortality and excess deaths compared with the general US population and identified targets to reduce future risk. METHODS: In this multi-institutional, hospital-based, retrospective cohort study, late mortality (death ≥5 years from diagnosis) and specific causes of death were evaluated in 34 230 5-year survivors of childhood cancer diagnosed at an age younger than 21 years from 1970 to 1999 at 31 institutions in the USA and Canada; median follow-up from diagnosis was 29 years (range 5-48) in the Childhood Cancer Survivor Study. Demographic, self-reported modifiable lifestyle (ie, smoking, alcohol, physical activity, and BMI) and cardiovascular risk factors (ie, hypertension, diabetes, and dyslipidaemia) associated with health-related mortality (which excludes death from primary cancer and external causes and includes death from late effects of cancer therapy) were evaluated. FINDINGS: 40-year cumulative all-cause mortality was 23·3% (95% CI 22·7-24·0), with 3061 (51·2%) of 5916 deaths from health-related causes. Survivors 40 years or more from diagnosis experienced 131 excess health-related deaths per 10 000 person-years (95% CI 111-163), including those due to the top three causes of health-related death in the general population: cancer (absolute excess risk per 10 000 person-years 54, 95% CI 41-68), heart disease (27, 18-38), and cerebrovascular disease (10, 5-17). Healthy lifestyle and absence of hypertension and diabetes were each associated with a 20-30% reduction in health-related mortality independent of other factors (all p values ≤0·002). INTERPRETATION: Survivors of childhood cancer are at excess risk of late mortality even 40 years from diagnosis, due to many of the leading causes of death in the US population. Modifiable lifestyle and cardiovascular risk factors associated with reduced risk for late mortality should be part of future interventions. FUNDING: US National Cancer Institute and the American Lebanese Syrian Associated Charities.

Association analysis of self-reported outcomes with a validated subset.

In health-science research, outcomes ascertained through surveys and interviews are subject to potential bias with respect to the true outcome status, which is only ascertainable with clinical and laboratory assessment. This measurement error may lead to biased inference when evaluating associations between exposures and outcomes of interest. Here, we consider a cohort study in which the outcome of interest is ascertained via questionnaire, subject to imperfect ascertainment, but where a subset of participants also have a clinically assessed, validated outcome available. This presents a methodological opportunity to address potential bias. Specifically, we constructed the likelihood in two parts, one using the validated subset and the other using a subset without validation. This work expands on that proposed by Pepe and enables inference with standard statistical software. Weighted generalized linear model estimates for our method and maximum likelihood estimates (MLE) for Pepe's method were computed, and the statistical inference was based on the standard large-sample likelihood theory. We compare the finite sample performance of two approaches through Monte Carlo simulations. This methodological work was motivated by a large cohort study of long-term childhood cancer survivors, allowing us to provide a relevant application example where we examined the association between clinical factors and chronic health conditions.

Physical capacity in children and adolescents with newly diagnosed cancer: A systematic review and meta-analysis.

OBJECTIVE: To review the body of evidence on cardiorespiratory fitness, muscle strength, and physical performance in children with newly diagnosed cancer, five databases (MEDLINE, Embase, CINAHL, CENTRAL, and Web of Science) were searched on December 19, 2022. METHODS: Thirteen studies, embodying 594 participants within 1 month of cancer diagnosis and 3674 healthy controls were included. Eighteen different outcomes on cardiorespiratory fitness (n = 2), muscle strength (n = 5), physical performance (n = 10), and adverse events (n = 1) were analyzed. RESULTS: Fifteen out of 17 outcomes on physical capacity showed severe impairments compared with healthy controls. Where possible, random-effects meta-analysis was conducted to synthesize the results. No adverse events were reported related to testing. CONCLUSION: Children with cancer have impaired cardiorespiratory fitness, muscle strength, and physical performance within the first month after diagnosis. However, the evidence is based on a small number of studies with large clinical heterogeneity, limiting the certainty of evidence.

Development and validation of age-specific risk prediction models for primary ovarian insufficiency in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort.

BACKGROUND: Female survivors of childhood cancer are at risk for primary ovarian insufficiency (POI), defined as the cessation of gonadal function before the age of 40 years. We aimed to develop and validate models to predict age-specific POI risk among long-term survivors of childhood cancer. METHODS: To develop models to predict age-specific POI risk for the ages of 21-40 years, we used data from the Childhood Cancer Survivor Study (CCSS). Female survivors aged 18 years or older at their latest follow-up, with self-reported menstrual history information and free of subsequent malignant neoplasms within 5 years of diagnosis, were included. We evaluated models that used algorithms based on statistical or machine learning to consider all predictors, including cancer treatments. Cross-validated prediction performance metrics (eg, area under the receiver operating characteristic curve [AUROC]) were compared to select the best-performing models. For external validation of the models, we used data from 5-year survivors in the St Jude Lifetime Cohort (SJLIFE) with ovarian status clinically ascertained using hormone measurements (menopause defined by follicle stimulating hormone >30 mIU/mL and oestradiol <17 pg/mL) and medical chart or questionnaire review. We also evaluated an SJLIFE-based polygenic risk score for POI among 1985 CCSS survivors with genotype data available. FINDINGS: 7891 female CCSS survivors (922 with POI) were included in the development of the POI risk prediction model, and 1349 female SJLIFE survivors (101 with POI) were included in the validation study. Median follow-up from cancer diagnosis was 23·7 years (IQR 18·3-30·0) in CCSS and 15·1 years (10·4-22·9) in SJLIFE. Between the ages of 21 and 40 years, POI prevalence increased from 7·9% (95% CI 7·3-8·5) to 18·6% (17·3-20·0) in CCSS and 7·3% (5·8-8·9) to 14·9% (11·6-19·1) in SJLIFE. Age-specific logistic regression models considering ovarian radiation dosimetry or prescribed pelvic and abdominal radiation dose, along with individual chemotherapy predictors, performed well in CCSS. In the SJLIFE validation, the prescribed radiation dose model performed well (AUROC 0·88-0·95), as did a simpler model that considered any exposures to pelvic or abdominal radiotherapy or alkylators (0·82-0·90). Addition of the polygenic risk predictor significantly improved the average positive predictive value (from 0·76 [95% CI 0·63-0·89] to 0·87 [0·80-0·94]; p=0·029) among CCSS survivors treated with ovarian radiation and chemotherapy. INTERPRETATION: POI risk prediction models using treatment information showed robust prediction performance in adult survivors of childhood cancer. FUNDING: Canadian Institutes of Health Research, US National Cancer Institute.

Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study.

BACKGROUND: Carriers of cancer predisposing variants are at an increased risk of developing subsequent malignant neoplasms among those who have survived childhood cancer. We aimed to investigate whether cancer predisposing variants contribute to the risk of subsequent malignant neoplasm-related late mortality (5 years or more after diagnosis). METHODS: In this analysis, data were included from two retrospective cohort studies, St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS), with prospective follow-up of patients who were alive for at least 5 years after diagnosis with childhood cancer (ie, long-term childhood cancer survivors) with corresponding germline whole genome or whole exome sequencing data. Cancer predisposing variants affecting 60 genes associated with well-established autosomal-dominant cancer-predisposition syndromes were characterised. Subsequent malignant neoplasms were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 with modifications. Cause-specific late mortality was based on linkage with the US National Death Index and systematic cohort follow up. Fine-Gray subdistribution hazard models were used to estimate subsequent malignant neoplasm-related late mortality starting from the first biospecimen collection, treating non-subsequent malignant neoplasm-related deaths as a competing risk, adjusting for genetic ancestry, sex, age at diagnosis, and cancer treatment exposures. SJLIFE (NCT00760656) and CCSS (NCT01120353) are registered with ClinicalTrials.gov. FINDINGS: 12 469 (6172 male and 6297 female) participants were included, 4402 from the SJLIFE cohort (median follow-up time since collection of the first biospecimen 7·4 years [IQR 3·1-9·4]) and 8067 from the CCSS cohort (median follow-up time since collection of the first biospecimen 12·6 years [2·2-16·6]). 641 (5·1%) of 12 469 participants carried cancer predisposing variants (294 [6·7%] in the SJLIFE cohort and 347 [4·3%] in the CCSS cohort), which were significantly associated with an increased severity of subsequent malignant neoplasms (CTCAE grade ≥4 vs grade <4: odds ratio 2·15, 95% CI 1·18-4·19, p=0·0085). 263 (2·1%) subsequent malignant neoplasm-related deaths (44 [1·0%] in the SJLIFE cohort; and 219 [2·7%] in the CCSS cohort) and 426 (3·4%) other-cause deaths (103 [2·3%] in SJLIFE; and 323 [4·0%] in CCSS) occurred. Cumulative subsequent malignant neoplasm-related mortality at 10 years after the first biospecimen collection in carriers of cancer predisposing variants was 3·7% (95% CI 1·2-8·5) in SJLIFE and 6·9% (4·1-10·7) in CCSS versus 1·5% (1·0-2·1) in SJLIFE and 2·1% (1·7-2·5) in CCSS in non-carriers. Carrying a cancer predisposing variant was associated with an increased risk of subsequent malignant neoplasm-related mortality (SJLIFE: subdistribution hazard ratio 3·40 [95% CI 1·37-8·43]; p=0·0082; CCSS: 3·58 [2·27-5·63]; p<0·0001). INTERPRETATION: Identifying participants at increased risk of subsequent malignant neoplasms via genetic counselling and clinical genetic testing for cancer predisposing variants and implementing early personalised cancer surveillance and prevention strategies might reduce the substantial subsequent malignant neoplasm-related mortality burden. FUNDING: American Lebanese Syrian Associated Charities and US National Institutes of Health.

Dietary supplement use among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort Study.

BACKGROUND: Adult survivors of childhood cancer have poor adherence to nutrition guidelines and inadequate intake of dietary vitamins D and E, potassium, fiber, magnesium, and calcium. The contribution of vitamin and mineral supplement use to total nutrient intake in this population is unclear. METHODS: We examined the prevalence and dose of nutrient intake among 2570 adult survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study, and the association of dietary supplement use with treatment exposures, symptom burden, and quality of life. RESULTS: Nearly 40% of the adult survivors of cancer survivors reported regular use of dietary supplements. Although cancer survivors who used dietary supplements were less likely to have inadequate intake of several nutrients, they were also more likely to have excessive intake (total nutrient intake ≥ tolerable upper intake levels) of folate (15.4% vs. 1.3%), vitamin A (12.2% vs. 0.2%), iron (27.8% vs. 1.2%), zinc (18.6% vs. 1%), and calcium (5.1% vs. 0.9%) compared with survivors who did not use dietary supplements (all p < 0.05). Treatment exposures, symptom burden, and physical functioning were not associated with supplement use, whereas emotional well-being and vitality were positively associated with supplement use among childhood cancer survivors. CONCLUSIONS: Supplement use is associated with both inadequate and excessive intake of specific nutrients, but positively impacts aspects of quality of life among childhood cancer survivors.

Health behavior profiles in young survivors of childhood cancer: Findings from the St. Jude Lifetime Cohort Study.

BACKGROUND: There is limited understanding of associations between a combination of health behaviors (physical activity, sedentary/screen-time, diet) and cardiometabolic health risk factors, physical performance, and emotional health among young (<18) childhood cancer survivors (CCS). The aims of this research were to address this gap by 1) deriving health behavior adherence profiles among CCS, and 2) examining associations among demographic, diagnosis and/or treatment exposures, cardiometabolic, physical performance, and emotional functioning with health behavior profile membership. METHODS: Participants included 397 CCS (≥5 years post-diagnosis; 10-17 years old) enrolled in the St. Jude Lifetime Cohort Study who completed physical health evaluations and questionnaires assessing health behaviors and psychological functioning. Latent profile analysis was used to derive profiles of health behavior adherence. Logistic regression and t-tests were used to examine mean-level differences and associations between profile membership with demographic, diagnosis, treatment exposures, cardiometabolic health, psychological functioning, and physical performance. RESULTS: Two profiles emerged: inactive-unhealthy-diet ("IU") and active-sedentary-unhealthy-diet ("ASU") to guidelines. More participants in IU demonstrated higher resting heart rate (mean [M], 76.54; SD = 12.00) and lower motor proficiency scores (M = 34.73; SD = 29.15) compared to ASU (resting heart rate, M = 71.95, SD = 10.74; motor proficiency, M = 50.40, SD = 31.02). CONCLUSIONS: CCS exhibited low adherence to multiple health behavior guidelines, with adherence patterns differentially associated with cardiometabolic health (i.e., resting heart rate) and physical performance. However, robust protection against all health variables was not observed. Findings suggest interventions designed to improve health outcomes should target multiple health behaviors simultaneously. PLAIN LANGUAGE SUMMARY: Pediatric cancer survivors are at-risk for detrimental health outcomes associated with cancer and treatment. Engagement in healthy lifestyle behaviors serves to reduce health vulnerabilities among adult survivors but less is known about associations with lifestyle behaviors on young survivors. This study documents patterns of lifestyle behaviors among survivors of pediatric cancer, factors that increase susceptibility to nonadherence, and associations among lifestyle behaviors and health indicators.

Generalizability of "GWAS Hits" in Clinical Populations: Lessons from Childhood Cancer Survivors.

With mounting interest in translating genome-wide association study (GWAS) hits from large meta-analyses (meta-GWAS) in diverse clinical settings, evaluating their generalizability in target populations is crucial. Here, we consider long-term survivors of childhood cancers from the St. Jude Lifetime Cohort Study, and we show the limited generalizability of 1,376 robust SNP associations reported in the general population across 12 complex anthropometric and cardiometabolic phenotypes (n = 2,231; observed-to-expected replication ratio = 0.70, p = 6.2 × 10-8). An examination of five comparable phenotypes in a second independent cohort of survivors from the Childhood Cancer Survivor Study corroborated the overall limited generalizability of meta-GWAS hits to survivors (n = 4,212; observed-to-expected replication ratio = 0.55, p = 5.6 × 10-15). Finally, in direct comparisons of survivor samples against independent equivalently powered general population samples from the UK Biobank, we consistently observed lower meta-GWAS hit replication rates and poorer polygenic risk score predictive performance in survivor samples for multiple phenotypes. As a possible explanation, we found that meta-GWAS hits were less likely to be replicated in survivors who had been exposed to cancer therapies that are associated with phenotype risk. Examination of complementary DNA methylation data in a subset of survivors revealed that treatment-related methylation patterns at genomic sites linked to meta-GWAS hits may disrupt established genetic signals in survivors.

Response-shift effects in childhood cancer survivors: A prospective study.

BACKGROUND: Treatment-related late effects can worsen over time among cancer survivors. Such worsening health states may trigger changes in internal standards, values, or conceptualization of quality-of-life (QOL). This "response-shift" phenomenon can jeopardize the validity of QOL assessment, and misrepresent QOL comparisons over time. This study tested response-shift effects in reporting future-health concerns among childhood cancer survivors who experienced progression in chronic health conditions (CHCs). METHODS: 2310 adult survivors of childhood cancer from St. Jude Lifetime Cohort Study completed a survey and clinical assessment at two or more timepoints. Based on 190 individual CHCs graded for adverse-event severity, global CHC burden was classified as "progression" or "non-progression". QOL was assessed using the SF-36TM eight domains and physical- and mental-component summary scores (PCS, MCS). A single global item measured concerns about future health. Random-effects models comparing survivors with and without progressive global CHC burden (progressors vs. non-progressors) evaluated response-shift effects (recalibration, reprioritization, reconceptualization) in reporting future-health concerns. RESULTS: Compared with non-progressors, progressors were more likely to de-emphasize (or downplay) overall physical and mental health in evaluating future-health concerns (p-values<0.05), indicating recalibration response-shift, and more likely to de-emphasize physical health earlier rather than later in follow-up (p-value<0.05), indicating reprioritization response-shift. There was evidence for a reconceptualization response-shift with progressor classification associated with worse-than-expected future-health concerns and physical health, and better-than-expected pain and role-emotional functioning (p-values<0.05). CONCLUSION: We identified three types of response-shift phenomena in reporting concerns about future health among childhood cancer survivors. Survivorship care or research should consider response-shift effects when interpreting changes in QOL over time.

Adverse childhood experiences and resilience in childhood and adolescent and young adult cancer patients.

Childhood and adolescent and young adult (AYA) cancer survivors experience poor health outcomes in adulthood. Adverse childhood experiences (ACEs) also portend poor health outcomes for the general population. Resilience can mitigate effects of ACEs. We examined the feasibility of assessing ACEs and resilience in childhood and AYA cancer patients. We also described occurrences of ACEs, resilience, and poor health outcomes. Of 52 participants, most rated their study experience favorably, with privacy in answering sensitive questions. Half reported ACEs, and those with ACEs had lower resilience; X2 (3, N = 52) = 9.4, p = .02. Further investigations of ACEs and resilience in larger cohorts are warranted to delineate associations with long-term health outcomes.

Assessment of proxy-reported responses as predictors of motor and sensory peripheral neuropathy in children with B-lymphoblastic leukemia.

Chemotherapy-induced peripheral neuropathy (CIPN), a common condition in children with acute lymphoblastic leukemia, can be challenging to diagnose. Using data from Children's Oncology Group AALL0932 physical function study, we sought to determine if parent/guardian proxy-reported responses from the Pediatric Outcomes Data Collection Instrument could identify children with motor or sensory CIPN diagnosed by physical/occupational therapists (PT/OT). Four variables moderately discriminated between children with and without motor CIPN (c-index 0.76, 95% confidence interval [CI]: 0.64-0.84), but sensory and optimism-corrected models had weak discrimination (c-index sensory models 0.65, 95% CI: 0.54-0.74). New proxy-report measures are needed to identify children with PT/OT diagnosed CIPN.

Physical activity and physical fitness assessments in adolescents and young adults diagnosed with cancer: a scoping review.

PURPOSE: This scoping review describes the assessment methodologies for physical activity (PA) and physical fitness assessments used in studies focusing on adolescents and young adults (AYAs) diagnosed with cancer. METHODS: A search of the literature was conducted in PubMed, CINAHL, Web of Science, and Cochrane Library following the PRISMA-ScR statement. A total of 34 studies were included in this review. RESULTS: PA was primarily assessed via self-reported questionnaires (30/34) either completed in-person (n = 17) or online (n = 13) at different time points and different stages along the cancer trajectory (i.e., from diagnosis onward). A total of 9 studies conducted a physical fitness assessment. CONCLUSIONS: PA and physical fitness measurements are key when trying to describe outcomes, assess for associations, track changes, measure intervention adherence, and test intervention efficacy and effectiveness. Considerable heterogeneity across studies was reported limiting the generation of formal recommendations or guidance for researchers, healthcare providers, and policy makers.

What Are Risk Factors for and Outcomes of Late Amputation After Treatment for Lower Extremity Sarcoma: A Childhood Cancer Survivor Study Report.

BACKGROUND: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas. QUESTIONS/PURPOSES: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis? METHODS: The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys. RESULTS: More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups. CONCLUSION: There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient. LEVEL OF EVIDENCE: Level III, therapeutic study.

Factors for poor oral health in long-term childhood cancer survivors.

BACKGROUND: Survivors of childhood cancer are at risk for therapy-related dental diseases. The purpose of the study was to investigate the associations between clinical, socioeconomic, and demographic factors and oral diseases in the St. Jude Lifetime Cohort (SJLIFE) participants. METHODS: We performed a retrospective medical chart review and evaluated longitudinal self-reported dental outcomes in 4856 childhood cancer survivors and 591 community controls participating in the St. Jude Lifetime Cohort (SJLIFE) study. Univariate and multivariable logistic regression models were used to assess the impact of socioeconomic factors, treatment exposures and patient demographics on dental outcomes. RESULTS: Cancer survivors were more likely to report microdontia (odds ratio (OR) = 7.89, 95% confidence interval (CI) [4.64, 14.90]), abnormal root development (OR = 6.19, CI [3.38, 13.00]), hypodontia (OR = 2.75, CI [1.83, 4.33]), enamel hypoplasia (OR = 4.24, CI [2.9, 6.49]), xerostomia (OR = 7.72, CI [3.27, 25.10]), severe gingivitis (OR = 2.04, CI [1.43, 3.03]), and ≥ 6 missing teeth (OR = 3.73, CI [2.46, 6.00]) compared to controls without cancer history. Survivors who received classic alkylating agents (OR = 1.6, CI [1.36, 1.88]), anthracycline antibiotics (OR = 1.22, CI [1.04, 1.42] or radiation therapy potentially exposing the oral cavity (OR = 1.48, CI [1.26, 1.72]) were more likely to report at least one dental health problem after controlling for socioeconomic factors, age at last follow-up and diagnosis, other treatment exposures, and access to dental services. Survivors who had radiation therapy potentially exposing the oral cavity (OR = 1.52, CI [1.25, 1.84]) were also more likely to report at least one soft tissue abnormality after controlling for socioeconomic factors, age at last follow-up and diagnosis, other treatment exposures, and access and utilization of dental services. CONCLUSIONS: Childhood cancer survivors have a higher prevalence of oral-dental abnormalities than the controls without a cancer history. Cancer treatment, socioeconomic factors, and access to oral health care contribute to the prevalence of dental abnormalities.

Childhood Neurotoxicity and Brain Resilience to Adverse Events during Adulthood.

OBJECTIVE: This study used childhood cancer survivors as a novel model to study whether children who experience central nervous system (CNS) injury are at higher risk for neurocognitive impairment associated with subsequent late onset chronic health conditions (CHCs). METHODS: Adult survivors of childhood cancer (n = 2,859, ≥10 years from diagnosis, ≥18 years old) completed a comprehensive neurocognitive battery and clinical examination. Neurocognitive impairment was defined as age-adjusted z score < 10th percentile. Participants impaired on ≥3 tests had global impairment. CHCs were graded using the Common Terminology Criteria for Adverse Events v4.3 (grade 1, mild; 2, moderate; 3, severe/disabling; 4, life-threatening) and were combined into a severity/burden score by frequency and grade (none/low, medium, high, and very high). A total of 1,598 survivors received CNS-directed therapy including cranial radiation, intrathecal methotrexate, or neurosurgery. Logistic regression estimated the odds of neurocognitive impairment associated with severity/burden score and grade 2 to 4 conditions, stratified by CNS treatment. RESULTS: CNS-treated survivors performed worse than non-CNS-treated survivors on all neurocognitive tests and were more likely to have global neurocognitive impairment (46.9% vs 35.3%, p < 0.001). After adjusting for demographic and treatment factors, there was a dose-response association between severity/burden score and global neurocognitive impairment, but only among CNS-treated survivors (high odds ratio [OR] = 2.24, 95% confidence interval [CI] = 1.42-3.53; very high OR = 4.07, 95% CI = 2.30-7.17). Cardiovascular and pulmonary conditions were associated with processing speed, executive function, and memory impairments in CNS-treated but not non-CNS-treated survivors who were impacted by neurologic conditions. INTERPRETATION: Reduced cognitive/brain reserve associated with CNS-directed therapy during childhood may make survivors vulnerable to adverse cognitive effects of cardiopulmonary conditions during adulthood. ANN NEUROL 2021;89:534-545.